|
1
|
Zhang R, Chong R, Yang S, He K, Wen Q. Bioequivalence of generic and branded ibrutinib capsules in healthy Chinese volunteers under fasting and fed conditions: a randomized, four-period, fully replicated, crossover study. Expert Opin Drug Metab Toxicol 2025:1-9. [PMID: 40264436 DOI: 10.1080/17425255.2025.2496459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND The aim of this study was to evaluate the bioequivalence of the test and reference products of ibrutinib capsule (140 mg). RESEARCH DESIGN AND METHODS This was a fully replicated crossover study that included 100 healthy Chinese volunteers (50 in the fasting BE study and 50 in the fed BE study). Subjects were assigned to receive a single dose of test or reference product in each treatment period. The bioequivalence of main PK parameters (Cmax, AUC0-t, and AUC0-∞) was evaluated using either the average bioequivalence (ABE) approach or the reference-scaled average bioequivalence (RSABE) approach, depending on the within-subject standard deviation of the reference product (SWR) estimated in the study. RESULTS RSABE approach was applied to Cmax as the corresponding SWR value exceeded the cutoff value of 0.294, while ABE approach was applied to AUC0-t and AUC0-∞ as the corresponding SWR values were less than 0.294. All three PK parameters (Cmax, AUC0-t, and AUC0-∞) met the bioequivalence acceptance criteria in both fasting and fed studies. CONCLUSIONS The test and reference products of ibrutinib capsule are bioequivalent under both fasting and fed conditions. This study also confirmed high intra-subject variability for the Cmax of ibrutinib. CLINICAL TRIAL REGISTRATION http://www.chinadrugtrials.org.cn/index.html identifier is CTR20202168.
Collapse
Affiliation(s)
- Rong Zhang
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
- Department of Clinical Pharmacology, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China
| | - Rui Chong
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
- Department of Clinical Pharmacology, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China
| | - Shaomei Yang
- Clinical Research Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Kun He
- Clinical Research Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qing Wen
- Clinical Research Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| |
Collapse
|
|
2
|
Tian C, Du H, Sha W, Wu L, Yu Z, Song H, Shen Z, Dai Y, Li S, Mei W, Zhao Z, Diao Y, Jiang H, Li H, Chen Z. Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2- a]quinoxalin-4(5 H)-one Derivatives as Potent and Orally Available Noncovalent Bruton's Tyrosine Kinase (BTK) Inhibitors. J Med Chem 2025; 68:8841-8860. [PMID: 40191988 DOI: 10.1021/acs.jmedchem.5c00439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2025]
Abstract
Bruton's tyrosine kinase (BTK) is a therapeutic target for B-cell-driven malignancies. Most of the approved covalent BTK inhibitors are associated with treatment limitations due to off-target toxicity and drug resistance. Developing noncovalent BTK inhibitors is a promising strategy to address unmet clinical needs. Here, a novel series of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives were designed and synthesized as noncovalent BTK inhibitors. Among them, representative compound 9 exhibited potent BTK inhibitory activity (IC50 = 21.6 nM) and excellent selectivity against a panel of 468 kinases. Moreover, the oral exposure property of compound 9 was improved, and the antitumor efficacy of compound 9 (TGI = 64.4%) was superior to the lead S2 (TGI = 28.7%) and Ibrutinib (TGI = 41.1%) in the U-937 xenograft models at an oral dosage of 50 mg/kg. All these results suggest that compound 9 is a potent, selective, and orally available noncovalent BTK inhibitor worthy of further development.
Collapse
Affiliation(s)
- Chaoquan Tian
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Husheng Du
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Wenjie Sha
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Lingkang Wu
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zhixiao Yu
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Haoming Song
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zihao Shen
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yan Dai
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Shuhui Li
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Wenyi Mei
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zhenjiang Zhao
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yanyan Diao
- Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China
| | - Hualiang Jiang
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Honglin Li
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
- Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China
| | - Zhuo Chen
- School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| |
Collapse
|
|
3
|
Nugent KI, Huang L, Patel JN, Hertz DL. Pharmacogenetic associations of GATA4 and KCNQ1 with ibrutinib cardiovascular toxicity. Pharmacogenet Genomics 2025; 35:101-109. [PMID: 39832190 DOI: 10.1097/fpc.0000000000000558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Ibrutinib treatment is often complicated by cardiovascular side effects (CVSEs). The objective of this retrospective pharmacogenetic study is to replicate a previously reported association of 'high-risk' patients, who are homozygous carriers of at least two of GATA4 rs804280 AA, KCNQ1 rs163182 GG, and KCNQ1 rs2237895 AA, with increased risk of hypertension or atrial fibrillation, and explore associations for other pharmacogenes (e.g. CYP3A4 , CYP3A5 , CYP2D6 , and ABCB1 ) with ibrutinib CVSEs. Univariate associations with P < 0.05 were adjusted for significant pretreatment cardiovascular conditions. In total 57 patients were included in the analysis. In the primary analysis, 'high-risk' patients were not more likely to experience hypertension or atrial fibrillation (70 vs. 41%, chi-square P value = 0.06). In secondary analyses, 'high-risk' patients were more likely to experience any CVSE during treatment (75 vs. 41%, P = 0.013), develop a cardiac rhythm or function disorder (65 vs. 24%, P = 0.008), and have a treatment modification due to CVSE (45 vs. 8%, P = 0.004). Additionally, high-risk homozygous variant genotypes of KCNQ1 rs163182 GG and rs2237895 AA were each associated with an increased likelihood of treatment modifications due to CVSE (40 vs. 11%, P = 0.021 and 45 vs. 9%, P = 0.004, respectively) and cardiac rhythm or function disorders (60 vs. 27%, P = 0.037 and 60 vs. 27%, P = 0.037). This study found supportive evidence that 'high-risk' genotype was associated with increased ibrutinib CVSEs. Validation of these associations is necessary before prospective trials testing whether personalized ibrutinib treatment approaches improve clinical outcomes.
Collapse
Affiliation(s)
- Kelly I Nugent
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan
| | - Lyucheng Huang
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan
| | - Jai N Patel
- Department of Cancer Pharmacology and Pharmacogenomics, Atrium Health Levine Cancer Institute, Charlotte
- Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem
- Department of Cancer Biology, Atrium Health Wake Forest University School of Medicine, Charlotte, North Carolina, USA
| | - Daniel L Hertz
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan
| |
Collapse
|
|
4
|
Ysebaert L, Protin C, Obéric L, Beziat G, De Barros S, Bonneau B, Allal B, Yakoubi M, Quillet-Mary A, Despas F. Ibrutinib pharmacokinetics in B-lymphoproliferative disorders discloses exposure-related incidence of hypertension. J Hypertens 2025; 43:521-528. [PMID: 39835452 PMCID: PMC11789613 DOI: 10.1097/hjh.0000000000003937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 10/03/2024] [Accepted: 11/03/2024] [Indexed: 01/22/2025]
Abstract
OBJECTIVE Ibrutinib has been the first Bruton tyrosine kinase inhibitor (BTKi) authorized for the treatment of B-cell lymphoproliferative disorders (B-LPDs). Numerous publications have confirmed the efficacy of this orally administrated drug in chemo-free regimens for B-LPDs. They also reported several adverse events (AE) associated with ibrutinib treatment. Whether these AEs depended on ibrutinib exposure has however been seldom explored. METHODS In the study reported here, the incidence of AE was recorded in 92 patients with B-LPD (mostly chronic lymphocytic leukemia n = 79) for whom ibrutinib alone was proposed as fist line therapy. Moreover, a pharmacokinetics (PK) exploration was planned over one day after 1 month treatment. PK assays included drug and metabolite (DHD-ibrutinib) mean/median and maximal plasmatic concentrations as well as areas under the curve (AUE) data. RESULTS This PK evaluation was analyzed regarding AEs recorded over the first year of therapy, which were similar as in published reports. PK data disclosed a significant impact of ibrutinib exposure on infections but mostly on the occurrence of hypertension. The latter was mostly related to dihydrodiol-ibrutinib (DHD-ibrutinib) exposure. CONCLUSIONS These data suggest that a DHD-ibrutinib assay after one month of treatment could be interesting to consider a lower dosage for patients above maximal concentration thresholds for the drug, its metabolite or the sum of both. Whether this can be applied to newer BTKi remains to be explored but it could be important for patients to whom ibrutinib is proposed.
Collapse
Affiliation(s)
- Loïc Ysebaert
- Hematology Department, Institut Universitaire du Cancer de Toulouse-Oncopole, Center for Cancer Research of Toulouse (CRCT), Inserm UMR1037, IUC-Toulouse-Oncopole
- Center for Cancer Research of Toulouse (CRCT), UMR1037, Inserm-University Toulouse III Paul Sabatier-ERL5294 CNRS
| | - Caroline Protin
- Hematology Department, Institut Universitaire du Cancer de Toulouse-Oncopole, Center for Cancer Research of Toulouse (CRCT), Inserm UMR1037, IUC-Toulouse-Oncopole
| | - Lucie Obéric
- Hematology Department, Institut Universitaire du Cancer de Toulouse-Oncopole, Center for Cancer Research of Toulouse (CRCT), Inserm UMR1037, IUC-Toulouse-Oncopole
| | | | - Sandra De Barros
- Service de pharmacologie médicale et clinique, faculté de médecine, Centre Hospitalier Universitaire
| | - Baptiste Bonneau
- Service de pharmacologie médicale et clinique, faculté de médecine, Centre Hospitalier Universitaire
- Unité MeDatAS-CIC 1436, Service de Pharmacologie Médicale et Clinique, CHU de Toulouse, Faculté de Médecine, Université Toulouse III, 37 allées Jules Guesde, Toulouse
| | - Ben Allal
- Center for Cancer Research of Toulouse (CRCT), UMR1037, Université de Toulouse, Inserm, and Institut Claudius-Regaud, IUCT-Oncopole
| | - Malika Yakoubi
- Center for Cancer Research of Toulouse (CRCT), UMR1037, Université de Toulouse, Inserm, and Institut Claudius-Regaud, IUCT-Oncopole
| | - Anne Quillet-Mary
- Center for Cancer Research of Toulouse (CRCT), UMR1037, Inserm-University Toulouse III Paul Sabatier-ERL5294 CNRS
| | - Fabien Despas
- Service de pharmacologie médicale et clinique, faculté de médecine, Centre Hospitalier Universitaire
- Institute of Cardiovascular and Metabolic Diseases, National Institute of Health and Medical Research (Inserm), UMR-1048, Toulouse, France
| |
Collapse
|
|
5
|
Yao Y, Yan Y, Suman VJ, Dietz AB, Erskine CL, Dimou A, Markovic SN, McWilliams RR, Montane HN, Block MS. Phase I study of pembrolizumab in combination with ibrutinib for the treatment of unresectable or metastatic melanoma. Front Immunol 2025; 16:1491448. [PMID: 39967670 PMCID: PMC11832643 DOI: 10.3389/fimmu.2025.1491448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have been transformative in the treatment of patients with metastatic melanoma, but primary and secondary resistance to ICI treatment is common. One key mechanism for ICI resistance is the skewing of the immune response from a cytotoxic (Th1) to a chronic inflammatory (Th2) profile. The small molecule ibrutinib is a dual-target agent that inhibits Bruton's Tyrosine Kinase (BTK) and Interleukin-2-inducible T-cell Kinase (ITK), a key regulator of Th2 immunity. Therefore, combining ibrutinib and pembrolizumab could potentially induce an increase in Th1 immune polarity in melanoma patients. We hypothesize that the combination would be well-tolerated and might result in clinical benefit for patients with metastatic melanoma. The primary aim of this phase I study was to evaluate the safety, tolerability, and determine the maximum tolerated dose (MTD) of ibrutinib in combination with pembrolizumab in patients with metastatic melanoma. Methods A 3 + 3 phase I clinical trial was conducted in patients with unresectable Stage III or metastatic melanoma (stage IV) not amenable to local therapy. Pembrolizumab (200 mg/kg every 3 weeks) was combined with ibrutinib, administered orally at the dose assigned at the time of registration (140 mg daily, 280 mg daily, and 420 mg daily). Patients were treated until disease progression, intolerability, or patient decision to discontinue. Blood samples were collected after each cycle of treatment for immunophenotyping and Th1/Th2 polarity assessment based on immune response markers. Results Between January 31, 2017 and January 9, 2023, 17 patients were enrolled. The MTD of ibrutinib in combination with pembrolizumab was determined to be 420 mg daily. The adverse events leading to discontinuation included: grade 4 ALT and AST increase (1 pt, DL0); grade 4 ALT increase with grade 3 AST increase (1 pt, DL1); and grade 3 hyponatremia, hypoxia, and maculo-papular rash (1 pt, DL1). Three of the 16 patients treated had objective responses (2 partial responses, 1 complete response) lasting over 8 months. The median progression-free survival was 3 months, and median and overall survival was 1.8 years. The combination treatment did not result in consistent increase in Th1 immune polarity. Conclusion In conclusion, the maximum tolerated dose of ibrutinib in combination with pembrolizumab in patients with advanced or metastatic melanoma was established at 420 mg by mouth once daily. The combination was well-tolerated but did not result in a consistent increase in Th1 immune polarity; further investigation is needed to assess the relative clinical efficacy of this approach. (Funded by Pharmacyclics; ClinicalTrials.gov number: NCT03021460). Clinical trial registration www.clinicaltrials.gov, identifier NCT03021460.
Collapse
Affiliation(s)
- Yuan Yao
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Yiyi Yan
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL, United States
| | - Vera J. Suman
- Department of Health Sciences, Division of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
| | - Allan B. Dietz
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | | | - Anastasios Dimou
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Svetomir N. Markovic
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
| | | | | | - Matthew S. Block
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
| |
Collapse
|
|
6
|
Yerla RR, Manubolusurya S, Meganathan S, Madalapu V, Vaidyanathan G. Structural Elucidation of Novel Degradation Impurities of Ibrutinib in Ibrutinib Tablets Using Preparative Chromatography, LCMS, HRMS and 2D NMR Techniques. J Chromatogr Sci 2025; 63:bmae002. [PMID: 38336469 DOI: 10.1093/chromsci/bmae002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 12/25/2023] [Accepted: 01/14/2024] [Indexed: 02/12/2024]
Abstract
Ibrutinib is an orally administered compound that functions as an irreversible covalent inhibitor of the Bruton tyrosine kinase, an essential element in multiple cellular processes including B-cell differentiation, proliferation, migration, survival and apoptosis. The compound has been found to demonstrate efficacy against a range of B-cell malignancies. The drug product is available in oral tablet and capsule formulations. The drug degradation profiles of tablets dosage form were assessed in accordance with regulatory guidelines. The results indicate that the drug substance is susceptible to alkaline and oxidative stress. The oxidation degradation led to the identification of three significant unknown degradation impurities. The three compounds were isolated through the application of preparative liquid chromatography, and their structures were determined using analytical techniques such as liquid chromatography-mass spectrometry, high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Utilizing structural elucidation data, predictions were made regarding the composition of impurities, revealing them to be novel degradation impurities that bear structural resemblance to ibrutinib. Additionally, potential pathways for the formation of the impurities were proposed.
Collapse
Affiliation(s)
- Rajender Reddy Yerla
- Department of Chemistry, School of Science, GITAM Deemed to be University, Hyderabad, Telangana 502329, India
- Natco Research Centre, Natco Pharma Ltd., Sanathnagar, Hyderabad 500078, India
| | - Surendrababu Manubolusurya
- Department of Chemistry, School of Science, GITAM Deemed to be University, Hyderabad, Telangana 502329, India
| | | | - Veerababu Madalapu
- Natco Research Centre, Natco Pharma Ltd., Sanathnagar, Hyderabad 500078, India
| | - Gopal Vaidyanathan
- Natco Research Centre, Natco Pharma Ltd., Sanathnagar, Hyderabad 500078, India
| |
Collapse
|
|
7
|
Prakash Kamath P, Devanand Bangera P, Dhatri Kara D, Roychowdhury R, Tippavajhala VK, Rathnanand M. Formulation and evaluation of ibrutinib-loaded glycyrrhizic acid conjugated ovalbumin nanoparticles and ibrutinib-glycyrrhizic acid complex for improved oral bioavailability. Pharm Dev Technol 2024; 29:1185-1198. [PMID: 39642037 DOI: 10.1080/10837450.2024.2436190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/29/2024] [Accepted: 11/26/2024] [Indexed: 12/08/2024]
Abstract
The study aimed at enhancing the oral bioavailability of the BCS class 2 drug Ibrutinib (IBR), which exhibits low solubility (0.002 mg/mL) and high permeability (3.9% oral bioavailability). This was achieved through the formulation and evaluation of Ibrutinib-loaded Glycyrrhizic acid conjugated egg ovalbumin nanoparticles (IBR-GA-EA NPs) and Ibrutinib-Glycyrrhizic acid complex (IBR-GA-COMP). The formulation of Ibrutinib-Glycyrrhizic acid complex aimed to enhance the oral bioavailability of Ibrutinib. Lyophilized Ibrutinib-Glycyrrhizic acid complex was prepared and characterized through various studies including DSC, FTIR, in vitro release, and in vivo pharmacokinetics studies. DSC and FTIR confirmed successful formulation development. The nanoparticles exhibited spherical morphology with favourable characteristics: particle size of 194.10 nm, PDI of 0.22, and zeta potential of -33.96 mV. Encapsulation efficiency was 82.88%. In vitro release study displayed major improvement in drug release pattern compared to the free drug suspension. In vivo pharmacokinetic studies demonstrated 3.21-fold and 3.41-fold increase in the oral bioavailability of IBR-GA-EA NPs and IBR-GA-COMP, respectively, compared to IBR suspension alone. The formulated IBR-GA-EA NPs and IBR-GA-COMP are promising drug delivery methods as they successfully improve the solubility and oral bioavailability of Ibrutinib.
Collapse
Affiliation(s)
- Prateeksha Prakash Kamath
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Pragathi Devanand Bangera
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Divya Dhatri Kara
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | | | - Vamshi Krishna Tippavajhala
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Mahalaxmi Rathnanand
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| |
Collapse
|
|
8
|
Liang L, Zhang Z, You Q, Guo X. Recent advances in the design of small molecular drugs with acrylamides covalent warheads. Bioorg Med Chem 2024; 112:117902. [PMID: 39236467 DOI: 10.1016/j.bmc.2024.117902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 09/07/2024]
Abstract
In the development of covalent inhibitors, acrylamides warhead is one of the most popular classes of covalent warheads. In recent years, researchers have made different structural modifications to acrylamides warheads, resulting in the creation of fluorinated acrylamide warheads and cyano acrylamide warheads. These new warheads exhibit superior selectivity, intracellular accumulation, and pharmacokinetic properties. Additionally, although ketoamide warheads have been applied in the design of covalent inhibitors for viral proteins, it has not received sufficient attention. Combined with the studies in kinase inhibitors and antiviral drugs, this review presents the structural features and the progression of acrylamides warheads, offering a perspective on future research and development in this field.
Collapse
Affiliation(s)
- Luxia Liang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Ze Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Xiaoke Guo
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| |
Collapse
|
|
9
|
Shi JT, Hou SJ, Cheng L, Zhang HJ, Mu HX, Wang QS, Wang ZY, Chen SW. Discovery of novel coumarin-based KRAS-G12C inhibitors from virtual screening and Rational structural optimization. Bioorg Chem 2024; 148:107467. [PMID: 38772290 DOI: 10.1016/j.bioorg.2024.107467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/09/2024] [Accepted: 05/14/2024] [Indexed: 05/23/2024]
Abstract
KRAS-G12C inhibitors has been made significant progress in the treatment of KRAS-G12C mutant cancers, but their clinical application is limited due to the adaptive resistance, motivating development of novel structural inhibitors. Herein, series of coumarin derivatives as KRAS-G12C inhibitors were found through virtual screening and rational structural optimization. Especially, K45 exhibited strong antiproliferative potency on NCI-H23 and NCI-H358 cancer cells harboring KRAS-G12C with the IC50 values of 0.77 μM and 1.50 μM, which was 15 and 11 times as potent as positive drug ARS1620, respectively. Furthermore, K45 reduced the phosphorylation of KRAS downstream effectors ERK and AKT by reducing the active form of KRAS (KRAS GTP) in NCI-H23 cells. In addition, K45 induced cell apoptosis by increasing the expression of anti-apoptotic protein BAD and BAX in NCI-H23 cells. Docking studies displayed that the 3-naphthylmethoxy moiety of K45 extended into the cryptic pocket formed by the residues Gln99 and Val9, which enhanced the interaction with the KRAS-G12C protein. These results indicated that K45 was a potent KRAS-G12C inhibitor worthy of further study.
Collapse
Affiliation(s)
- Jian-Tao Shi
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Su-Juan Hou
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Lei Cheng
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Hao-Jie Zhang
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Hong-Xia Mu
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Qing-Shan Wang
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Zhao-Yang Wang
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China
| | - Shi-Wu Chen
- School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
| |
Collapse
|
|
10
|
Acharya B, Saha D, Armstrong D, Jabali B, Hanafi M, Herrera-Rueda A, Lakkaniga NR, Frett B. Kinase inhibitor macrocycles: a perspective on limiting conformational flexibility when targeting the kinome with small molecules. RSC Med Chem 2024; 15:399-415. [PMID: 38389874 PMCID: PMC10880908 DOI: 10.1039/d3md00457k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 12/10/2023] [Indexed: 02/24/2024] Open
Abstract
Methods utilized for drug discovery and development within the kinome have rapidly evolved since the approval of imatinib, the first small molecule kinase inhibitor. Macrocycles have received increasing interest as a technique to improve kinase inhibitor drug properties evident by the FDA approvals of lorlatinib, pacritinib, and repotrectinib. Compared to their acyclic counterparts, macrocycles can possess improved pharmacodynamic and pharmacokinetic properties. This review highlights clinical success stories when implementing macrocycles in kinase-based drug discovery and showcases that macrocyclization is a clinically validated drug discovery strategy when targeting the kinome.
Collapse
Affiliation(s)
- Baku Acharya
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
| | - Debasmita Saha
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
- Conrad Prebys Centre for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute San Diego CA USA
| | - Daniel Armstrong
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
| | - Baha'a Jabali
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
| | - Maha Hanafi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University Cairo 11526 Egypt
| | - Alan Herrera-Rueda
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
| | - Naga Rajiv Lakkaniga
- Department of Chemistry and Chemical Biology, Indian Institute of Technology (Indian School of Mines) Dhanbad India
| | - Brendan Frett
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
| |
Collapse
|
|
11
|
Serafim RAM, Gehringer M, Borsari C. Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond. Pharmaceuticals (Basel) 2024; 17:206. [PMID: 38399421 PMCID: PMC10891537 DOI: 10.3390/ph17020206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 01/31/2024] [Indexed: 02/25/2024] Open
Abstract
Covalent inhibitors have experienced a revival in medicinal chemistry and chemical biology in recent decades [...].
Collapse
Affiliation(s)
- Ricardo A. M. Serafim
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Matthias Gehringer
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) ‘Image-Guided & Functionally Instructed Tumor Therapies’, University of Tübingen, 72076 Tübingen, Germany
| | - Chiara Borsari
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy
| |
Collapse
|
|
12
|
Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, Chirino A, Jahn J, Sondhi AK, Gajewski S, Tan YS(M, Yung S, Urban A, Wang E, Han C, Mi X, Kim WJ, Sievers Q, Auger P, Bousquet H, Brathaban N, Bravo B, Gessner M, Guiducci C, Iuliano JN, Kane T, Mukerji R, Reddy PJ, Powers J, Sanchez Garcia de los Rios M, Ye J, Risso CB, Tsai D, Pardo G, Notti RQ, Pardo A, After M, Nawaratne V, Totiger TM, Pena-Velasquez C, Rhodes JM, Zelenetz AD, Alencar A, Roeker LE, Mehta S, Garippa R, Linley A, Soni RK, Skånland SS, Brown RJ, Mato AR, Hansen GM, Abdel-Wahab O, Taylor J. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science 2024; 383:eadi5798. [PMID: 38301010 PMCID: PMC11103405 DOI: 10.1126/science.adi5798] [Citation(s) in RCA: 54] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 12/08/2023] [Indexed: 02/03/2024]
Abstract
Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.
Collapse
Affiliation(s)
- Skye Montoya
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jessie Bourcier
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Hao Lu
- Nurix Therapeutics, San Francisco, CA, USA
| | - Meghan C. Thompson
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexandra Chirino
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jacob Jahn
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anya K. Sondhi
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | | | | | - Aleksandra Urban
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Eric Wang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Cuijuan Han
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Xiaoli Mi
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Won Jun Kim
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Quinlan Sievers
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Paul Auger
- Nurix Therapeutics, San Francisco, CA, USA
| | | | | | | | | | | | | | - Tim Kane
- Nurix Therapeutics, San Francisco, CA, USA
| | | | | | | | | | - Jordan Ye
- Nurix Therapeutics, San Francisco, CA, USA
| | - Carla Barrientos Risso
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Daniel Tsai
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Gabriel Pardo
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ryan Q. Notti
- Laboratory of Molecular Electron Microscopy, Rockefeller University, New York, NY, USA
| | - Alejandro Pardo
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Maurizio After
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Vindhya Nawaratne
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Tulasigeri M. Totiger
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Camila Pena-Velasquez
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joanna M. Rhodes
- division of Hematology-Oncology, Department of Medicine at Zucker School of Medicine at Hofstra/Northwell, CLL Research and Treatment Center, Lake Success, NY, USA
| | - Andrew D. Zelenetz
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alvaro Alencar
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Lindsey E. Roeker
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sanjoy Mehta
- Gene Editing and Screening Core Facility, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA
| | - Ralph Garippa
- Gene Editing and Screening Core Facility, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA
| | - Adam Linley
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Rajesh Kumar Soni
- Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Sigrid S. Skånland
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | | | - Anthony R. Mato
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Omar Abdel-Wahab
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Justin Taylor
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| |
Collapse
|
|
13
|
Ramsey JR, Shelton PM, Heiss TK, Olinares PDB, Vostal LE, Soileau H, Grasso M, Casebeer SW, Adaniya S, Miller M, Sun S, Huggins DJ, Myers RW, Chait BT, Vinogradova EV, Kapoor TM. Using a Function-First "Scout Fragment"-Based Approach to Develop Allosteric Covalent Inhibitors of Conformationally Dynamic Helicase Mechanoenzymes. J Am Chem Soc 2024; 146:62-67. [PMID: 38134034 PMCID: PMC10958666 DOI: 10.1021/jacs.3c10581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2023]
Abstract
Helicases, classified into six superfamilies, are mechanoenzymes that utilize energy derived from ATP hydrolysis to remodel DNA and RNA substrates. These enzymes have key roles in diverse cellular processes, such as translation, ribosome assembly, and genome maintenance. Helicases with essential functions in certain cancer cells have been identified, and helicases expressed by many viruses are required for their pathogenicity. Therefore, helicases are important targets for chemical probes and therapeutics. However, it has been very challenging to develop chemical inhibitors for helicases, enzymes with high conformational dynamics. We envisioned that electrophilic "scout fragments", which have been used in chemical proteomic studies, could be leveraged to develop covalent inhibitors of helicases. We adopted a function-first approach, combining enzymatic assays with enantiomeric probe pairs and mass spectrometry, to develop a covalent inhibitor that selectively targets an allosteric site in SARS-CoV-2 nsp13, a superfamily-1 helicase. Further, we demonstrate that scout fragments inhibit the activity of two human superfamily-2 helicases, BLM and WRN, involved in genome maintenance. Together, our findings suggest an approach to discover covalent inhibitor starting points and druggable allosteric sites in conformationally dynamic mechanoenzymes.
Collapse
Affiliation(s)
- Jared R. Ramsey
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10021, United States
- Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, United States
| | - Patrick M.M Shelton
- Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, United States
| | - Tyler K. Heiss
- Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, United States
| | - Paul Dominic B. Olinares
- Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY 10065, United States
| | - Lauren E. Vostal
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10021, United States
- Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, United States
| | - Heather Soileau
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10021, United States
- Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, United States
| | - Michael Grasso
- Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, United States
| | - Sara W. Casebeer
- Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, United States
| | - Stephanie Adaniya
- Laboratory of Chemical Immunology and Proteomics, The Rockefeller University, New York, NY 10065, United States
| | - Michael Miller
- Sanders Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065, United States
| | - Shan Sun
- Sanders Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065, United States
| | - David J. Huggins
- Sanders Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065, United States
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, United States
| | - Robert W. Myers
- Sanders Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065, United States
| | - Brian T. Chait
- Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY 10065, United States
| | - Ekaterina V. Vinogradova
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10021, United States
- Laboratory of Chemical Immunology and Proteomics, The Rockefeller University, New York, NY 10065, United States
| | - Tarun M. Kapoor
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10021, United States
- Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, United States
| |
Collapse
|
|
14
|
Wang S, Ballard TE, Christopher LJ, Foti RS, Gu C, Khojasteh SC, Liu J, Ma S, Ma B, Obach RS, Schadt S, Zhang Z, Zhang D. The Importance of Tracking "Missing" Metabolites: How and Why? J Med Chem 2023; 66:15586-15612. [PMID: 37769129 DOI: 10.1021/acs.jmedchem.3c01293] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2023]
Abstract
Technologies currently employed to find and identify drug metabolites in complex biological matrices generally yield results that offer a comprehensive picture of the drug metabolite profile. However, drug metabolites can be missed or are captured only late in the drug development process. This could be due to a variety of factors, such as metabolism that results in partial loss of the molecule, covalent bonding to macromolecules, the drug being metabolized in specific human tissues, or poor ionization in a mass spectrometer. These scenarios often draw a great deal of attention from chemistry, safety assessment, and pharmacology. This review will summarize scenarios of missing metabolites, why they are missing, and associated uncovering strategies from deeper investigations. Uncovering previously missed metabolites can have ramifications in drug development with toxicological and pharmacological consequences, and knowledge of these can help in the design of new drugs.
Collapse
Affiliation(s)
- Shuai Wang
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - T Eric Ballard
- Takeda Development Center Americas, Inc., 35 Landsdowne St, Cambridge, Massachusetts 02139, United States
| | - Lisa J Christopher
- Department of Clinical Pharmacology, Pharmacometrics, Disposition & Bioanalysis, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, New Jersey 08543, United States
| | - Robert S Foti
- Preclinical Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
| | - Chungang Gu
- Drug Metabolism and Pharmacokinetics, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States
| | - S Cyrus Khojasteh
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Joyce Liu
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Shuguang Ma
- Drug Metabolism and Pharmacokinetics, Pliant Therapeutics, 260 Littlefield Avenue, South San Francisco, California 94080, United States
| | - Bin Ma
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - R Scott Obach
- Pharmacokinetics, Dynamics, and Metabolism, Pfizer, Inc., Eastern Point Road, Groton, Connecticut 06340, United States
| | - Simone Schadt
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Strasse 124, 4070 Basel, Switzerland
| | - Zhoupeng Zhang
- DMPK Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Donglu Zhang
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
| |
Collapse
|
|
15
|
Duan ZK, Guo SS, Ye L, Gao ZH, Liu D, Yao GD, Song SJ, Huang XX. Discovery of Michael reaction acceptors from the leaves of Ailanthus altissima by a modified tactic. PHYTOCHEMISTRY 2023; 215:113858. [PMID: 37709157 DOI: 10.1016/j.phytochem.2023.113858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 09/09/2023] [Accepted: 09/09/2023] [Indexed: 09/16/2023]
Abstract
Structural characteristics-guided investigation of Ailanthus altissima (Mill.) Swingle resulted in the isolation and identification of seven undescribed potential Michael reaction acceptors (1-7). Ailanlactone A (1) possesses an unusual 1,7-epoxy-11,12-seco quassinoid core. Ailanterpene B (6) was a rare guaianolide-type sesquiterpene with a 5/6/6/6-fused skeleton. Their structures were determined through extensive analysis of physiochemical and spectroscopic data, quantum chemical calculations, and single crystal X-ray crystallographic technology using Cu Kα radiation. The cytotoxic activities of isolates on HepG2 and Hep3B cells were evaluated in vitro. Encouragingly, ailanaltiolide K (4) showed significant cytotoxicity against Hep3B cells with IC50 values of 1.41 ± 0.21 μM, whose covalent binding mode was uncovered in silico.
Collapse
Affiliation(s)
- Zhi-Kang Duan
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Shan-Shan Guo
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Li Ye
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Zhi-Heng Gao
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Dai Liu
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Guo-Dong Yao
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Shao-Jiang Song
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Xiao-Xiao Huang
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province China; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province China; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
| |
Collapse
|
|
16
|
Niezni D, Taub-Tabib H, Harris Y, Sason H, Amrusi Y, Meron-Azagury D, Avrashami M, Launer-Wachs S, Borchardt J, Kusold M, Tiktinsky A, Hope T, Goldberg Y, Shamay Y. Extending the boundaries of cancer therapeutic complexity with literature text mining. Artif Intell Med 2023; 145:102681. [PMID: 37925210 DOI: 10.1016/j.artmed.2023.102681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 08/30/2023] [Accepted: 10/03/2023] [Indexed: 11/06/2023]
Abstract
Drug combination therapy is a main pillar of cancer therapy. As the number of possible drug candidates for combinations grows, the development of optimal high complexity combination therapies (involving 4 or more drugs per treatment) such as RCHOP-I and FOLFIRINOX becomes increasingly challenging due to combinatorial explosion. In this paper, we propose a text mining (TM) based tool and workflow for rapid generation of high complexity combination treatments (HCCT) in order to extend the boundaries of complexity in cancer treatments. Our primary objectives were: (1) Characterize the existing limitations in combination therapy; (2) Develop and introduce the Plan Builder (PB) to utilize existing literature for drug combination effectively; (3) Evaluate PB's potential in accelerating the development of HCCT plans. Our results demonstrate that researchers and experts using PB are able to create HCCT plans at much greater speed and quality compared to conventional methods. By releasing PB, we hope to enable more researchers to engage with HCCT planning and demonstrate its clinical efficacy.
Collapse
Affiliation(s)
- Danna Niezni
- Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | | | - Yuval Harris
- Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Hagit Sason
- Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Yakir Amrusi
- Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Dana Meron-Azagury
- Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Maytal Avrashami
- Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Shaked Launer-Wachs
- Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | | | - M Kusold
- Allen Institute for AI, Seattle, USA
| | | | - Tom Hope
- Allen Institute for AI, Tel Aviv, Israel; The Hebrew University, Jerusalem, Israel
| | - Yoav Goldberg
- Allen Institute for AI, Tel Aviv, Israel; Bar-Ilan University, Ramat-Gan, Israel
| | - Yosi Shamay
- Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel.
| |
Collapse
|
|
17
|
Ilyinskii PO, Roy C, Michaud A, Rizzo G, Capela T, Leung SS, Kishimoto TK. Readministration of high-dose adeno-associated virus gene therapy vectors enabled by ImmTOR nanoparticles combined with B cell-targeted agents. PNAS NEXUS 2023; 2:pgad394. [PMID: 38024395 PMCID: PMC10673641 DOI: 10.1093/pnasnexus/pgad394] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/06/2023] [Indexed: 12/01/2023]
Abstract
Tolerogenic ImmTOR nanoparticles encapsulating rapamycin have been demonstrated to mitigate immunogenicity of adeno-associated virus (AAV) gene therapy vectors, enhance levels of transgene expression, and enable redosing of AAV at moderate vector doses of 2 to 5E12 vg/kg. However, recent clinical trials have often pushed AAV vector doses 10-fold to 50-fold higher, with serious adverse events observed at the upper range. Here, we assessed combination therapy of ImmTOR with B cell-targeting drugs for the ability to increase the efficiency of redosing at high vector doses. The combination of ImmTOR with a monoclonal antibody against B cell activation factor (aBAFF) exhibited strong synergy leading to more than a 5-fold to 10-fold reduction of splenic mature B cells and plasmablasts while increasing the fraction of pre-/pro-B cells. In addition, this combination dramatically reduced anti-AAV IgM and IgG antibodies, thus enabling four successive AAV administrations at doses up to 5E12 vg/kg and at least two AAV doses at 5E13 vg/kg, with the transgene expression level in the latter case being equal to that observed in control animals receiving a single vector dose of 1E14 vg/kg. Similar synergistic effects were seen with a combination of ImmTOR and a Bruton's tyrosine kinase inhibitor, ibrutinib. These results suggest that ImmTOR could be combined with B cell-targeting agents to enable repeated vector administrations as a potential strategy to avoid toxicities associated with vector doses above 1E14 vg/kg.
Collapse
Affiliation(s)
| | | | | | - Gina Rizzo
- Selecta Biosciences, Watertown, MA 02472, USA
| | | | | | | |
Collapse
|
|
18
|
Wu CP, Hsiao SH, Wu YS. Perspectives on drug repurposing to overcome cancer multidrug resistance mediated by ABCB1 and ABCG2. Drug Resist Updat 2023; 71:101011. [PMID: 37865067 DOI: 10.1016/j.drup.2023.101011] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/07/2023] [Accepted: 10/08/2023] [Indexed: 10/23/2023]
Abstract
The overexpression of the human ATP-binding cassette (ABC) transporters in cancer cells is a common mechanism involved in developing multidrug resistance (MDR). Unfortunately, there are currently no approved drugs specifically designed to treat multidrug-resistant cancers, making MDR a significant obstacle to successful chemotherapy. Despite over two decades of research, developing transporter-specific inhibitors for clinical use has proven to be a challenging endeavor. As an alternative approach, drug repurposing has gained traction as a more practical method to discover clinically effective modulators of drug transporters. This involves exploring new indications for already-approved drugs, bypassing the lengthy process of developing novel synthetic inhibitors. In this context, we will discuss the mechanisms of ABC drug transporters ABCB1 and ABCG2, their roles in cancer MDR, and the inhibitors that have been evaluated for their potential to reverse MDR mediated by these drug transporters. Our focus will be on providing an up-to-date report on approved drugs tested for their inhibitory activities against these drug efflux pumps. Lastly, we will explore the challenges and prospects of repurposing already approved medications for clinical use to overcome chemoresistance in patients with high tumor expression of ABCB1 and/or ABCG2.
Collapse
Affiliation(s)
- Chung-Pu Wu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan.
| | - Sung-Han Hsiao
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yu-Shan Wu
- Department of Chemistry, Tunghai University, Taichung 40704, Taiwan.
| |
Collapse
|
|
19
|
Mak JWY, Law AWH, Law KWT, Ho R, Cheung CKM, Law MF. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies in the targeted therapy era. World J Gastroenterol 2023; 29:4942-4961. [PMID: 37731995 PMCID: PMC10507505 DOI: 10.3748/wjg.v29.i33.4942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/22/2023] [Accepted: 08/15/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatitis due to hepatitis B virus (HBV) reactivation can be serious and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. Patients with inactive and even resolved HBV infection still have persistence of HBV genomes in the liver. The expression of these silent genomes is controlled by the immune system. Suppression or ablation of immune cells, most importantly B cells, may lead to reactivation of seemingly resolved HBV infection. Thus, all patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen. Patients found to be positive for HBsAg should be given prophylactic antiviral therapy. For patients with resolved HBV infection, there are two approaches. The first is pre-emptive therapy guided by serial HBV DNA monitoring, and treatment with antiviral therapy as soon as HBV DNA becomes detectable. The second approach is prophylactic antiviral therapy, particularly for patients receiving high-risk therapy, especially anti-CD20 monoclonal antibody or hematopoietic stem cell transplantation. Entecavir and tenofovir are the preferred antiviral choices. Many new effective therapies for hematological malignancies have been introduced in the past decade, for example, chimeric antigen receptor (CAR)-T cell therapy, novel monoclonal antibodies, bispecific antibody drug conjugates, and small molecule inhibitors, which may be associated with HBV reactivation. Although there is limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBsAg-positive patients receiving novel treatments, including Bruton's tyrosine kinase inhibitors, B-cell lymphoma 2 inhibitors, and CAR-T cell therapy. Further studies are needed to determine the risk of HBV reactivation with these agents and the best prophylactic strategy.
Collapse
Affiliation(s)
- Joyce Wing Yan Mak
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
| | | | | | - Rita Ho
- Department of Medicine, North District Hospital, Hong Kong 852, China
| | - Carmen Ka Man Cheung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
| | - Man Fai Law
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
| |
Collapse
|
|
20
|
Byun DP, Ritchie J, Jung Y, Holewinski R, Kim HR, Tagirasa R, Ivanic J, Weekley CM, Parker MW, Andresson T, Yoo E. Covalent Inhibition by a Natural Product-Inspired Latent Electrophile. J Am Chem Soc 2023; 145:11097-11109. [PMID: 37183434 PMCID: PMC10719761 DOI: 10.1021/jacs.3c00598] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
Strategies to target specific protein cysteines are critical to covalent probe and drug discovery. 3-Bromo-4,5-dihydroisoxazole (BDHI) is a natural product-inspired, synthetically accessible electrophilic moiety that has previously been shown to react with nucleophilic cysteines in the active site of purified enzymes. Here, we define the global cysteine reactivity and selectivity of a set of BDHI-functionalized chemical fragments using competitive chemoproteomic profiling methods. Our study demonstrates that BDHIs capably engage reactive cysteine residues in the human proteome and the selectivity landscape of cysteines liganded by BDHI is distinct from that of haloacetamide electrophiles. Given its tempered reactivity, BDHIs showed restricted, selective engagement with proteins driven by interactions between a tunable binding element and the complementary protein sites. We validate that BDHI forms covalent conjugates with glutathione S-transferase Pi (GSTP1) and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), emerging anticancer targets. BDHI electrophile was further exploited in Bruton's tyrosine kinase (BTK) inhibitor design using a single-step late-stage installation of the warhead onto acrylamide-containing compounds. Together, this study expands the spectrum of optimizable chemical tools for covalent ligand discovery and highlights the utility of 3-bromo-4,5-dihydroisoxazole as a cysteine-reactive electrophile.
Collapse
Affiliation(s)
- David P Byun
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
| | - Jennifer Ritchie
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
| | - Yejin Jung
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
| | - Ronald Holewinski
- Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biochemical Research, Frederick, Maryland 21702, United States
| | - Hong-Rae Kim
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
| | - Ravichandra Tagirasa
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
| | - Joseph Ivanic
- Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland 21702, United States
| | - Claire M Weekley
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Michael W Parker
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia
- Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia
| | - Thorkell Andresson
- Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biochemical Research, Frederick, Maryland 21702, United States
| | - Euna Yoo
- Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
| |
Collapse
|
|
21
|
Schaefer D, Cheng X. Recent Advances in Covalent Drug Discovery. Pharmaceuticals (Basel) 2023; 16:ph16050663. [PMID: 37242447 DOI: 10.3390/ph16050663] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/10/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Generally, the formation of covalent bonds that target proteins can offer drugs diverse advantages in terms of target selectivity, drug resistance, and administration concentration. The most important factor for covalent inhibitors is the electrophile (warhead), which dictates selectivity, reactivity, and the type of protein binding (i.e., reversible or irreversible) and can be modified/optimized through rational designs. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be 'undruggable'. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus.
Collapse
Affiliation(s)
- Daniel Schaefer
- Buchmann Institute for Molecular Life Sciences, Chemical Biology, Goethe University Frankfurt am Main, Max-von-Laue-Strasse 15. R. 3.652, 60438 Frankfurt am Main, Germany
- Pharmaceutical Chemistry, Goethe University Frankfurt am Main, 60438 Frankfurt am Main, Germany
| | - Xinlai Cheng
- Buchmann Institute for Molecular Life Sciences, Chemical Biology, Goethe University Frankfurt am Main, Max-von-Laue-Strasse 15. R. 3.652, 60438 Frankfurt am Main, Germany
- Pharmaceutical Chemistry, Goethe University Frankfurt am Main, 60438 Frankfurt am Main, Germany
- Frankfurt Cancer Institute, 60596 Frankfurt am Main, Germany
| |
Collapse
|
|
22
|
Luo W, Li C, Wu J, Tang L, Wang X, Zhang Y, Wu Z, Huang Z, Xu J, Kang Y, Xiong W, Deng J, Hu Y, Mei H. Bruton tyrosine kinase inhibitors preserve anti-CD19 chimeric antigen receptor T-cell functionality and reprogram tumor micro-environment in B-cell lymphoma. Cytotherapy 2023:S1465-3249(23)00066-X. [PMID: 37074239 DOI: 10.1016/j.jcyt.2023.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/02/2023] [Accepted: 03/10/2023] [Indexed: 04/20/2023]
Abstract
BACKGROUND AIMS Combination therapy is being actively explored to improve the efficacy and safety of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy, among which Bruton tyrosine kinase inhibitors (BTKIs) are highly expected. BTKIs may modulate T-cell function and remodel the tumor micro-environment (TME), but the exact mechanisms involved and the steps required to transform different BTKIs into clinical applications need further investigation. METHODS We examined the impacts of BTKIs on T-cell and CART19 phenotype and functionality in vitro and further explored the mechanisms. We evaluated the efficacy and safety of CART19 concurrent with BTKIs in vitro and in vivo. Moreover, we investigated the effects of BTKIs on TME in a syngeneic lymphoma model. RESULTS Here we identified that the three BTKIs, ibrutinib, zanubrutinib and orelabrutinib, attenuated CART19 exhaustion mediated by tonic signaling, T-cell receptor (TCR) activation and antigen stimulation. Mechanistically, BTKIs markedly suppressed CD3-ζ phosphorylation of both chimeric antigen receptor and TCR and downregulated the expression of genes associated with T-cell activation signaling pathways. Moreover, BTKIs decreased interleukin 6 and tumor necrosis factor alpha release in vitro and in vivo. In a syngeneic lymphoma model, BTKIs reprogrammed macrophages to the M1 subtype and polarized T helper (Th) cells toward the Th1 subtype. CONCLUSIONS Our data revealed that BTKIs preserved T-cell and CART19 functionality under persistent antigen exposure and further demonstrated that BTKI administration was a potential strategy for mitigating cytokine release syndrome after CART19 treatment. Our study lays the experimental foundation for the rational application of BTKIs combined with CART19 in clinical practice.
Collapse
Affiliation(s)
- Wenjing Luo
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenggong Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianghua Wu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Tang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xindi Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinqiang Zhang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuolin Wu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhongpei Huang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Xu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Kang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Xiong
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Jun Deng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Heng Mei
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
23
|
Co-Targeting of BTK and TrxR as a Therapeutic Approach to the Treatment of Lymphoma. Antioxidants (Basel) 2023; 12:antiox12020529. [PMID: 36830087 PMCID: PMC9952695 DOI: 10.3390/antiox12020529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a haematological malignancy representing the most diagnosed non-Hodgkin's lymphoma (NHL) subtype. Despite the approved chemotherapies available in clinics, some patients still suffer from side effects and relapsed disease. Recently, studies have reported the role of the Trx system and the BCR signalling pathway in cancer development and drug resistance. In this regard, we assessed a potential link between the two systems and evaluated the effects of [Au(d2pype)2]Cl (TrxR inhibitor) and ibrutinib (BTK inhibitor) alone and in combination on the cell growth of two DLBCL lymphoma cell lines, SUDHL2 and SUDHL4. In this study, we show higher expression levels of the Trx system and BCR signalling pathway in the DLBCL patient samples compared to the healthy samples. The knockdown of TrxR using siRNA reduced BTK mRNA and protein expression. A combination treatment with [Au(d2pype)2]Cl and ibrutinib had a synergistic effect on the inhibition of lymphoma cell proliferation, the activation of apoptosis, and, depending on lymphoma cell subtype, ferroptosis. Decreased BTK expression and the cytoplasmic accumulation of p65 were observed after the combination treatment in the DLBCL cells, indicating the inhibition of the NF-κB pathway. Thus, the co-targeting of BTK and TrxR may be an effective therapeutic strategy to consider for DLBCL treatment.
Collapse
|
|
24
|
Kumar A, Singh AK, Singh H, Vijayan V, Kumar D, Naik J, Thareja S, Yadav JP, Pathak P, Grishina M, Verma A, Khalilullah H, Jaremko M, Emwas AH, Kumar P. Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective. Pharmaceuticals (Basel) 2023; 16:299. [PMID: 37259442 PMCID: PMC9965678 DOI: 10.3390/ph16020299] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/26/2023] [Accepted: 01/28/2023] [Indexed: 07/30/2023] Open
Abstract
Cancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop safer and target-specific anticancer drugs. More than 85% of all physiologically active pharmaceuticals are heterocycles or contain at least one heteroatom. Nitrogen heterocycles constituting the most common heterocyclic framework. In this study, we have compiled the FDA approved heterocyclic drugs with nitrogen atoms and their pharmacological properties. Moreover, we have reported nitrogen containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, β-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines, which are used in the treatment of different types of cancer, concurrently covering the biochemical mechanisms of action and cellular targets.
Collapse
Affiliation(s)
- Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Harshwardhan Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Veena Vijayan
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Deepak Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Jashwanth Naik
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| | - Jagat Pal Yadav
- Pharmacology Research Laboratory, Faculty of Pharmaceutical Sciences, Rama University, Kanpur 209217, India
| | - Prateek Pathak
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, 454008 Chelyabinsk, Russia
| | - Maria Grishina
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, 454008 Chelyabinsk, Russia
| | - Amita Verma
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, India
| | - Habibullah Khalilullah
- Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unayzah 51911, Saudi Arabia
| | - Mariusz Jaremko
- Smart-Health Initiative and Red Sea Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
| | - Abdul-Hamid Emwas
- Core Labs, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda 151401, India
| |
Collapse
|
|
25
|
Zhang H, He F, Gao G, Lu S, Wei Q, Hu H, Wu Z, Fang M, Wang X. Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling. Molecules 2023; 28:molecules28030943. [PMID: 36770611 PMCID: PMC9920796 DOI: 10.3390/molecules28030943] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/02/2023] [Accepted: 01/05/2023] [Indexed: 01/20/2023] Open
Abstract
Kinases are among the most important families of biomolecules and play an essential role in the regulation of cell proliferation, apoptosis, metabolism, and other critical physiological processes. The dysregulation and gene mutation of kinases are linked to the occurrence and development of various human diseases, especially cancer. As a result, a growing number of small-molecule drugs based on kinase targets are being successfully developed and approved for the treatment of many diseases. The indole/azaindole/oxindole moieties are important key pharmacophores of many bioactive compounds and are generally used as excellent scaffolds for drug discovery in medicinal chemistry. To date, 30 ATP-competitive kinase inhibitors bearing the indole/azaindole/oxindole scaffold have been approved for the treatment of diseases. Herein, we summarize their research and development (R&D) process and describe their binding models to the ATP-binding sites of the target kinases. Moreover, we discuss the significant role of the indole/azaindole/oxindole skeletons in the interaction of their parent drug and target kinases, providing new medicinal chemistry inspiration and ideas for the subsequent development and optimization of kinase inhibitors.
Collapse
Affiliation(s)
- Haofan Zhang
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
| | - Fengming He
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
| | - Guiping Gao
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
- School of Medicine, Huaqiao University, Quanzhou 362021, China
| | - Sheng Lu
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
| | - Qiaochu Wei
- School of Public Health, Xiamen University, Xiamen 361102, China
| | - Hongyu Hu
- Xingzhi College, Zhejiang Normal University, Lanxi 321004, China
| | - Zhen Wu
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
| | - Meijuan Fang
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
- Correspondence: (M.F.); (X.W.)
| | - Xiumin Wang
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
- Correspondence: (M.F.); (X.W.)
| |
Collapse
|
|
26
|
Vandeveer GH, Arduini RM, Baker DP, Barry K, Bohnert T, Bowden-Verhoek JK, Conlon P, Cullen PF, Guan B, Jenkins TJ, Liao SY, Lin L, Liu YT, Marcotte D, Mertsching E, Metrick CM, Negrou E, Powell N, Scott D, Silvian LF, Hopkins BT. Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model. Bioorg Med Chem Lett 2023; 80:129108. [PMID: 36538993 DOI: 10.1016/j.bmcl.2022.129108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 11/27/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
For the past two decades, BTK a tyrosine kinase and member of the Tec family has been a drug target of significant interest due to its potential to selectively treat various B cell-mediated diseases such as CLL, MCL, RA, and MS. Owning to the challenges encountered in identifying drug candidates exhibiting the potency block B cell activation via BTK inhibition, the pharmaceutical industry has relied on the use of covalent/irreversible inhibitors to address this unmet medical need. Herein, we describe a medicinal chemistry campaign to identify structurally diverse reversible BTK inhibitors originating from HITS identified using a fragment base screen. The leads were optimized to improve the potency and in vivo ADME properties resulting in a structurally distinct chemical series used to develop and validate a novel in vivo CD69 and CD86 PD assay in rodents.
Collapse
Affiliation(s)
| | | | | | - Kevin Barry
- Medicinal Chemistry, Cambridge, MA 02142, USA
| | - Tonika Bohnert
- Drug Metabolism & Pharmacokinetics, Cambridge, MA 02142, USA
| | | | | | | | - Bing Guan
- Medicinal Chemistry, Cambridge, MA 02142, USA
| | | | - Shu-Yu Liao
- Biophysics and Structural Biology, Cambridge, MA 02142, USA
| | - Lin Lin
- Technical development, Cambridge, MA 02142, USA
| | | | | | | | | | - Ella Negrou
- Immunology, Biogen, 225 Binney Street, Cambridge, MA 02142, USA
| | - Noel Powell
- Medicinal Chemistry, Cambridge, MA 02142, USA
| | | | | | | |
Collapse
|
|
27
|
Kozaki R, Yasuhiro T, Kato H, Murai J, Hotta S, Ariza Y, Sakai S, Fujikawa R, Yoshida T. Investigation of the anti-tumor mechanism of tirabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, by phosphoproteomics and transcriptomics. PLoS One 2023; 18:e0282166. [PMID: 36897912 PMCID: PMC10004634 DOI: 10.1371/journal.pone.0282166] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 02/09/2023] [Indexed: 03/11/2023] Open
Abstract
Tirabrutinib is a highly selective Bruton's tyrosine kinase (BTK) inhibitor used to treat hematological malignancies. We analyzed the anti-tumor mechanism of tirabrutinib using phosphoproteomic and transcriptomic methods. It is important to check the drug's selectivity against off-target proteins to understand the anti-tumor mechanism based on the on-target drug effect. Tirabrutinib's selectivity was evaluated by biochemical kinase profiling assays, peripheral blood mononuclear cell stimulation assays, and the BioMAP system. Next, in vitro and in vivo analyses of the anti-tumor mechanisms were conducted in activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cells followed by phosphoproteomic and transcriptomic analyses. In vitro kinase assays showed that, compared with ibrutinib, tirabrutinib and other second-generation BTK inhibitors demonstrated a highly selective kinase profile. Data from in vitro cellular systems showed that tirabrutinib selectively affected B-cells. Tirabrutinib inhibited the cell growth of both TMD8 and U-2932 cells in correlation with the inhibition of BTK autophosphorylation. Phosphoproteomic analysis revealed the downregulation of ERK and AKT pathways in TMD8. In the TMD8 subcutaneous xenograft model, tirabrutinib showed a dose-dependent anti-tumor effect. Transcriptomic analysis indicated that IRF4 gene expression signatures had decreased in the tirabrutinib groups. In conclusion, tirabrutinib exerted an anti-tumor effect by regulating multiple BTK downstream signaling proteins, such as NF-κB, AKT, and ERK, in ABC-DLBCL.
Collapse
Affiliation(s)
- Ryohei Kozaki
- Discovery and Research, Ono Pharmaceutical Co., Ltd, Osaka, Japan
- * E-mail:
| | - Tomoko Yasuhiro
- Discovery and Research, Ono Pharmaceutical Co., Ltd, Osaka, Japan
| | - Hikaru Kato
- Discovery and Research, Ono Pharmaceutical Co., Ltd, Osaka, Japan
| | - Jun Murai
- Discovery and Research, Ono Pharmaceutical Co., Ltd, Osaka, Japan
| | - Shingo Hotta
- Discovery and Research, Ono Pharmaceutical Co., Ltd, Osaka, Japan
| | - Yuko Ariza
- Discovery and Research, Ono Pharmaceutical Co., Ltd, Osaka, Japan
| | - Shunsuke Sakai
- Discovery and Research, Ono Pharmaceutical Co., Ltd, Osaka, Japan
| | - Ryu Fujikawa
- Discovery and Research, Ono Pharmaceutical Co., Ltd, Osaka, Japan
| | - Takao Yoshida
- Discovery and Research, Ono Pharmaceutical Co., Ltd, Osaka, Japan
| |
Collapse
|
|
28
|
Gu J, Wu Q, Zhang Q, You Q, Wang L. A decade of approved first-in-class small molecule orphan drugs: Achievements, challenges and perspectives. Eur J Med Chem 2022; 243:114742. [PMID: 36155354 DOI: 10.1016/j.ejmech.2022.114742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/01/2022] [Accepted: 09/01/2022] [Indexed: 12/01/2022]
Abstract
In the past decade (2011-2020), there was a growing interest in the discovery and development of orphan drugs for the treatment of rare diseases. However, rare diseases only account for a population of 0.65‰-1‰ which usually occur with previously unknown biological mechanisms and lack of specific therapeutics, thus to increase the demands for the first-in-class (FIC) drugs with new biological targets or mechanisms. Considering the achievements in the past 10 years, a total of 410 drugs were approved by U.S. Food and Drug Administration (FDA), which contained 151 FIC drugs and 184 orphan drugs, contributing to make up significant numbers of the approvals. Notably, more than 50% of FIC drugs are developed as orphan drugs and some of them have already been milestones in drug development. In this review, we aim to discuss the FIC small molecules for the development of orphan drugs case by case and highlight the R&D strategy with novel targets and scientific breakthroughs.
Collapse
Affiliation(s)
- Jinying Gu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qiuyu Wu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qiuyue Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Lei Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| |
Collapse
|
|
29
|
Elbezanti WO, Al-Odat OS, Chitren R, Singh JK, Srivastava SK, Gowda K, Amin S, Robertson GP, Nemmara VV, Jonnalagadda SC, Budak-Alpdogan T, Pandey MK. Development of a novel Bruton's tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells. Front Pharmacol 2022; 13:894535. [PMID: 36160379 PMCID: PMC9500300 DOI: 10.3389/fphar.2022.894535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
Despite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Bruton's tyrosine kinase (BTK) in MM stem cell-like cells is correlated with drug resistance and poor prognosis. We have developed a novel small BTK inhibitor, KS151, which is unique compared to other BTK inhibitors. Unlike ibrutinib, and the other BTK inhibitors such as acalabrutinib, orelabrutinib, and zanubrutinib that covalently bind to the C481 residue in the BTK kinase domain, KS151 can inhibit BTK activities without binding to C481. This feature of KS151 is important because C481 becomes mutated in many patients and causes drug resistance. We demonstrated that KS151 inhibits in vitro BTK kinase activities and is more potent than ibrutinib. Furthermore, by performing a semi-quantitative, sandwich-based array for 71-tyrosine kinase phosphorylation, we found that KS151 specifically inhibits BTK. Our western blotting data showed that KS151 inhibits BTK signaling pathways and is effective against bortezomib-resistant cells as well as MM stem cell-like cells. Moreover, KS151 potentiates the apoptotic response of bortezomib, lenalidomide, and panobinostat in both MM and stem cell-like cells. Interestingly, KS151 inhibits stemness markers and is efficient in inhibiting Nanog and Gli1 stemness markers even when MM cells were co-cultured with bone marrow stromal cells (BMSCs). Overall, our results show that we have developed a novel BTK inhibitor effective against the stem cell-like population, and potentiates the response of chemotherapeutic agents.
Collapse
Affiliation(s)
- Weam Othman Elbezanti
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States
- Department of Hematology, MD Anderson Cancer Center at Cooper, Cooper Health University, Camden, NJ, United States
| | - Omar S. Al-Odat
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, United States
| | - Robert Chitren
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, United States
| | | | | | - Krishne Gowda
- Department of Pharmacology, Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, United States
| | - Shantu Amin
- Department of Pharmacology, Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, United States
| | - Gavin P. Robertson
- Department of Pharmacology, Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, United States
| | - Venkatesh V. Nemmara
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, United States
| | - Subash C. Jonnalagadda
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, United States
| | - Tulin Budak-Alpdogan
- Department of Hematology, MD Anderson Cancer Center at Cooper, Cooper Health University, Camden, NJ, United States
| | - Manoj K. Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States
| |
Collapse
|
|
30
|
Bilge S, Dogan-Topal B, Taskin Tok T, Atici EB, Sınağ A, Ozkan SA. Investigation of the interaction between anticancer drug ibrutinib and double-stranded DNA by electrochemical and molecular docking techniques. Microchem J 2022. [DOI: 10.1016/j.microc.2022.107622] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
|
|
31
|
Jin Y, Zou Y, Hu Y, Han Y, Zhang Z, Zhang W. Azole-Directed Cobalt-Catalyzed Asymmetric Hydrogenation of Alkenes. Chemistry 2022; 28:e202201517. [PMID: 35622378 DOI: 10.1002/chem.202201517] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Indexed: 12/11/2022]
Abstract
The azole-directed cobalt-catalyzed asymmetric hydrogenation of alkenes has been developed with high efficiency. With this approach, chiral pyrazole compounds were obtained in quantitative yields and excellent enantioselectivities (up to 99 % ee) under mild conditions, and the hydrogenation was conducted on a gram scale with up to 2000 TON. Several useful applications were demonstrated including the convenient introduction of β-chirality to a drug intermediate containing an azole ring.
Collapse
Affiliation(s)
- Yue Jin
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China
| | - Yashi Zou
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China
| | - Yanhua Hu
- Frontier Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China
| | - Yunxi Han
- Frontier Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China
| | - Zhenfeng Zhang
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China
| | - Wanbin Zhang
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China.,Frontier Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China
| |
Collapse
|
|
32
|
Yang H, Xiang B, Song Y, Zhang H, Zhao W, Zou D, Lv F, Guo W, Liu A, Li C, Tan Z, Liu Y, Fu L, Guo H, Novotny W, Huang J, Li Y. Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma. Blood Adv 2022; 6:1629-1636. [PMID: 34638136 PMCID: PMC8941452 DOI: 10.1182/bloodadvances.2020003698] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 06/06/2021] [Indexed: 02/05/2023] Open
Abstract
The non-germinal center B-cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) has poor clinical outcomes. Bruton tyrosine kinase (BTK) inhibitors have established therapeutic activity in B-cell malignancies, with modest activity in DLBCL. Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in patients with relapsed or refractory (R/R) non-GCB DLBCL. The BGB-3111-207 study (NCT03145064) was a multicenter single-arm phase 2 study. Patients received twice-daily oral zanubrutinib, 160 mg, until disease progression or unacceptable toxicity. The primary end point was the overall response rate (ORR). Secondary end points included progression-free survival (PFS) and duration of response (DOR). Overall survival (OS) was an exploratory end point. Forty-one patients were enrolled in China after having progressed or not responded to prior therapy. At data cutoff, 4 patients continued treatment with 37 discontinuations. The median follow-up was 6.8 months, the ORR was 29.3%, and the complete response rate was 17.1%. Median DOR, PFS, and OS were 4.5, 2.8, and 8.4 months, respectively. Adverse events (AEs) leading to treatment discontinuation were reported in 4 patients, and grade ≥ 3 AEs were reported in 48.8% of patients. Major hemorrhage, atrial fibrillation, and/or flutter were not observed. Zanubrutinib demonstrated modest antitumor activity in non-GCB DLBCL, like other BTK inhibitors, as well as a safety profile consistent with previous studies. Through retrospective biomarker testing, potential antitumor activity was observed in patients with both CD79B and MYD88 mutations, who have inferior outcomes to immunochemotherapy. Future studies of zanubrutinib in R/R non-GCB DLBCL will focus on developing mechanism-based treatment combinations and biomarker-driven patient selection.
Collapse
Affiliation(s)
- Haiyan Yang
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China
| | - Bing Xiang
- Department of Hematology, West China Hospital, Sichuan Hospital, Chengdu, China
| | - Yuqin Song
- Department of Lymphoma, Beijing Cancer Hospital, Beijing, China
| | - Huilai Zhang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Weili Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dehui Zou
- Lymphoma Diagnosis and Therapy Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Fangfang Lv
- Department of Oncology, Fudan University Shanghai Cancer Hospital, Shanghai, China
| | - Wei Guo
- Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China
| | - Aichun Liu
- Department of Hematology and Lymphoma, Harbin Medical University Cancer Hospital, Harbin, China
| | - Caixia Li
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ziwen Tan
- BeiGene (Shanghai) Co., Ltd, Shanghai, China
- BeiGene USA, Inc., San Mateo, CA; and
| | - Yang Liu
- BeiGene (Shanghai) Co., Ltd, Shanghai, China
- BeiGene USA, Inc., San Mateo, CA; and
| | - Lina Fu
- BeiGene (Shanghai) Co., Ltd, Shanghai, China
- BeiGene USA, Inc., San Mateo, CA; and
| | - Haiyi Guo
- BeiGene (Shanghai) Co., Ltd, Shanghai, China
- BeiGene USA, Inc., San Mateo, CA; and
| | - William Novotny
- BeiGene (Shanghai) Co., Ltd, Shanghai, China
- BeiGene USA, Inc., San Mateo, CA; and
| | - Jane Huang
- BeiGene (Shanghai) Co., Ltd, Shanghai, China
- BeiGene USA, Inc., San Mateo, CA; and
| | - Yufu Li
- Department of Hematology, Henan Cancer Hospital, Zhengzhou, China
| |
Collapse
|
|
33
|
Kaur M, Kaur M, Bandopadhyay T, Sharma A, Priya A, Singh A, Banerjee B. Naturally occurring, natural product inspired and synthetic heterocyclic anti-cancer drugs. PHYSICAL SCIENCES REVIEWS 2022. [DOI: 10.1515/psr-2022-0003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Abstract
This chapter describes the importance and activity of a huge number of commercially available naturally occurring, natural product derived or synthetic heterocyclic anti-cancer drugs.
Collapse
Affiliation(s)
- Manmeet Kaur
- Department of Chemistry , Akal University , Talwandi Sabo , Bathinda , Punjab 151302 , India
| | - Mandeep Kaur
- Department of Chemistry , Akal University , Talwandi Sabo , Bathinda , Punjab 151302 , India
| | - Tania Bandopadhyay
- Completed MBBS from North Bengal Medical College and Hospital , Darjeeling , West Bengal , Pin-734432 , India
| | - Aditi Sharma
- Department of Chemistry , Akal University , Talwandi Sabo , Bathinda , Punjab 151302 , India
| | - Anu Priya
- Department of Chemistry , Akal University , Talwandi Sabo , Bathinda , Punjab 151302 , India
| | - Arvind Singh
- Department of Chemistry , Akal University , Talwandi Sabo , Bathinda , Punjab 151302 , India
| | - Bubun Banerjee
- Department of Chemistry , Akal University , Talwandi Sabo , Bathinda , Punjab 151302 , India
| |
Collapse
|
|
34
|
Mendes‐Bastos P, Brasileiro A, Kolkhir P, Frischbutter S, Scheffel J, Moñino‐Romero S, Maurer M. Bruton's tyrosine kinase inhibition-An emerging therapeutic strategy in immune-mediated dermatological conditions. Allergy 2022; 77:2355-2366. [PMID: 35175630 PMCID: PMC9545595 DOI: 10.1111/all.15261] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/08/2022] [Accepted: 02/14/2022] [Indexed: 02/06/2023]
Abstract
Bruton's tyrosine kinase (BTK), a member of the Tec kinase family, is critically involved in a range of immunological pathways. The clinical application of BTK inhibitors for B‐cell malignancies has proven successful, and there is strong rationale for the potential benefits of BTK inhibitors in some autoimmune and allergic conditions, including immune‐mediated dermatological diseases. However, the established risk‐to‐benefit profile of “first‐generation” BTK inhibitors cannot be extrapolated to these emerging, non‐oncological, indications. “Next‐generation” BTK inhibitors such as remibrutinib and fenebrutinib entered clinical development for chronic spontaneous urticaria (CSU); rilzabrutinib and tirabrutinib are being studied as potential treatments for pemphigus. Promising data from early‐phase clinical trials in CSU suggest potential for these agents to achieve strong pathway inhibition, which may translate into measurable clinical benefits, as well as other effects such as the disruption of autoantibody production. BTK inhibitors may help to overcome some of the shortcomings of monoclonal antibody treatments for immune‐mediated dermatological conditions such as CSU, pemphigus, and systemic lupus erythematosus. In addition, the use of BTK inhibitors may improve understanding of the pathophysiological roles of mast cells, basophils, and B cells in such conditions.
Collapse
Affiliation(s)
| | - Ana Brasileiro
- Department of Dermatology Hospital Santo António dos Capuchos Centro Hospitalar Universitário Lisboa Central Lisbon Portugal
- NOVA Medical School Universidade NOVA de Lisboa Lisbon Portugal
| | - Pavel Kolkhir
- Dermatological Allergology, Allergie‐Centrum‐Charité, Department of Dermatology and Allergy, Charité‐Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt‐Universität zu Berlin, and Berlin Institute of Health Berlin Germany
- Division of Immune‐Mediated Skin Diseases I.M. Sechenov First Moscow State Medical University (Sechenov University) Moscow Russia
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology Berlin Germany
| | - Stefan Frischbutter
- Dermatological Allergology, Allergie‐Centrum‐Charité, Department of Dermatology and Allergy, Charité‐Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt‐Universität zu Berlin, and Berlin Institute of Health Berlin Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology Berlin Germany
| | - Jörg Scheffel
- Dermatological Allergology, Allergie‐Centrum‐Charité, Department of Dermatology and Allergy, Charité‐Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt‐Universität zu Berlin, and Berlin Institute of Health Berlin Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology Berlin Germany
| | - Sherezade Moñino‐Romero
- Dermatological Allergology, Allergie‐Centrum‐Charité, Department of Dermatology and Allergy, Charité‐Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt‐Universität zu Berlin, and Berlin Institute of Health Berlin Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology Berlin Germany
| | - Marcus Maurer
- Dermatological Allergology, Allergie‐Centrum‐Charité, Department of Dermatology and Allergy, Charité‐Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt‐Universität zu Berlin, and Berlin Institute of Health Berlin Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology Berlin Germany
| |
Collapse
|
|
35
|
Li W, Zhang J, Wang M, Dong R, Zhou X, Zheng X, Sun L. Pyrimidine-fused Dinitrogenous Penta-heterocycles as a Privileged Scaffold for Anti-Cancer Drug Discovery. Curr Top Med Chem 2022; 22:284-304. [PMID: 35021973 DOI: 10.2174/1568026622666220111143949] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/30/2021] [Accepted: 12/30/2021] [Indexed: 11/22/2022]
Abstract
Pyrimidine-fused derivatives that are the inextricable part of DNA and RNA play a key role in the normal life cycle of cells. Pyrimidine-fused dinitrogenous penta-heterocycles including pyrazolopyrimidines and imidazopyrimidines is a special class of pyrimidine-fused compounds contributing to an important portion in anti-cancer drug discovery, which have been discovered as core structure for promising anti-cancer agents used in clinic or clinical evaluations. Pyrimidine-fused dinitrogenous penta-heterocycles have become one privileged scaffold for anti-cancer drug discovery. This review consists of the recent progress of pyrimidine-fused dinitrogenous penta-heterocycles as anti-cancer agents and their synthetic strategies. In addition, this review also summarizes some key structure-activity relationships (SARs) of pyrimidine-fused dinitrogenous penta-heterocycle derivatives as anti-cancer agents.
Collapse
Affiliation(s)
- Wen Li
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Jinyang Zhang
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Min Wang
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Ru Dong
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xin Zhou
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xin Zheng
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Liping Sun
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| |
Collapse
|
|
36
|
Evaluation of Ibrutinib Cardiotoxicity By Comparative Use of Speckle-Tracking Technique and Biomarkers. Am J Ther 2022; 29:e50-e55. [PMID: 34994349 DOI: 10.1097/mjt.0000000000001463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Ibrutinib, a relatively new antineoplastic agent, has multiple cardiovascular effects that are still insufficiently known and evaluated, including subclinical myocardial damage. STUDY QUESTION The present study aims to assess the role of the myocardial strain, alone and in combination with cardiac biomarkers, in the early detection of ibrutinib-induced cardiotoxicity. STUDY DESIGN We included 31 outpatients with normal left ventricular ejection fraction (LVEF) on ibrutinib, in a tertiary University Hospital between 2019 and 2020, and evaluated them at inclusion and after 3 months. MEASURES AND OUTCOMES Data on myocardial strain, cardiac biomarkers [high-sensitive troponin T (hs TnT) and N-terminal probrain natriuretic peptide (NT-proBNP)], and ambulatory electrocardiographic monitoring were collected. RESULTS Myocardial deformation decreased significantly (P < 0.001) at later evaluation and hs TnT and NT-proBNP increased significantly (P = 0.019 and P = 0.03, respectively). The increase in hs TnT correlated with the increase in the left ventricle global longitudinal strain (LVGLS); in other words, it correlated with the decrease in myocardial deformation. No association was found between LVGLS increase and the increase in NT-proBNP. LVGLS modification was not significantly influenced by age, anemia, or arrhythmia burden quantified by 24-hour Holter monitoring (P = 0.747, P = 0.072, respectively; P = 0.812). LVEF did not change significantly during follow-up. CONCLUSIONS In patients on ibrutinib, evaluation of myocardial strain is useful in identifying early cardiac drug toxicity, surpassing the sensitivity and specificity limits of LVEF. In these patients, concomitant assessment of hs TnT increases the predictive power for subclinical myocardial involvement.
Collapse
|
|
37
|
Lu X, Smaill JB, Patterson AV, Ding K. Discovery of Cysteine-targeting Covalent Protein Kinase Inhibitors. J Med Chem 2021; 65:58-83. [PMID: 34962782 DOI: 10.1021/acs.jmedchem.1c01719] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Small molecule covalent kinase inhibitors (CKIs) have entered a new era in drug discovery, which have the advantage for sustained target inhibition and high selectivity. An increased understanding of binding kinetics of CKIs and discovery of additional irreversible and reversible-covalent cysteine-targeted warheads has inspired the development of this area. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative CKIs, which are categorized by the location of the target cysteine within seven main regions of the kinase: the front region, the glycine rich loop (P-loop), the hinge region, the DFG region, the activation loop (A-loop), the catalytic loop (C-loop), and the remote loop. The emphasis is placed on the design and optimization strategies of CKIs that are generated by addition of a warhead to a reversible lead/inhibitor scaffold. In addition, we address the challenges facing this area of drug discovery.
Collapse
Affiliation(s)
- Xiaoyun Lu
- School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Jeff B Smaill
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, New Zealand
| | - Adam V Patterson
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, New Zealand
| | - Ke Ding
- School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| |
Collapse
|
|
38
|
FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review. Cancers (Basel) 2021; 14:cancers14010087. [PMID: 35008250 PMCID: PMC8750348 DOI: 10.3390/cancers14010087] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/16/2021] [Accepted: 12/20/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Hematological malignancies are diseases involving the abnormal production of blood cells. The aim of the study is to collect comprehensive information on new drugs used in the treatment of blood cancers which have introduced into therapy in the last decade. The approved drugs were analyzed for their structures and their biological activity mechanisms. Abstract Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug Administration (FDA) in the period between 2011 and 2021 for the treatment of hematological malignancies. Forty of them have also been approved by the European Medicines Agency (EMA). We analyzed the FDA-approved drugs by investigating both their structures and mechanisms of action. It should be emphasized that the number of targeted drugs was significantly higher (46 drugs) than chemotherapy agents (6 drugs). We highlight recent advances in the design of drugs that are used to treat hematological malignancies, which make them more effective and less toxic.
Collapse
|
|
39
|
Cheng M, Yang F, Liu J, Yang D, Zhang S, Yu Y, Jiang S, Dong M. Tyrosine Kinase Inhibitors-Induced Arrhythmias: From Molecular Mechanisms, Pharmacokinetics to Therapeutic Strategies. Front Cardiovasc Med 2021; 8:758010. [PMID: 34869670 PMCID: PMC8639698 DOI: 10.3389/fcvm.2021.758010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/25/2021] [Indexed: 12/27/2022] Open
Abstract
With the development of anti-tumor drugs, tyrosine kinase inhibitors (TKIs) are an indispensable part of targeted therapy. They can be superior to traditional chemotherapeutic drugs in selectivity, safety, and efficacy. However, they have been found to be associated with serious adverse effects in use, such as myocardial infarction, fluid retention, hypertension, and rash. Although TKIs induced arrhythmia with a lower incidence than other cardiovascular diseases, much clinical evidence indicated that adequate attention and management should be provided to patients. This review focuses on QT interval prolongation and atrial fibrillation (AF) which are conveniently monitored in clinical practice. We collected data about TKIs, and analyzed the molecule mechanism, discussed the actual clinical evidence and drug-drug interaction, and provided countermeasures to QT interval prolongation and AF. We also pooled data to show that both QT prolongation and AF are related to their multi-target effects. Furthermore, more than 30 TKIs were approved by the FDA, but most of the novel drugs had a small sample size in the preclinical trial and risk/benefit assessments were not perfect, which led to a suspension after listing, like nilotinib. Similarly, vandetanib exhibits the most significant QT prolongation and ibrutinib exhibits the highest incidence in AF, but does not receive enough attention during treatment.
Collapse
Affiliation(s)
- Mengfei Cheng
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Fang Yang
- The First Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jiahui Liu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dan Yang
- Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shuo Zhang
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yang Yu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shuai Jiang
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| |
Collapse
|
|
40
|
Dou D, Sha W, Diao Y, Su R, Qiao Y, Yu Z, Zhao Z, Li H, Chen Z, Xu Y. Discovery of pyrido[3,4-b]indol-1-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors. Bioorg Chem 2021; 119:105541. [PMID: 34910982 DOI: 10.1016/j.bioorg.2021.105541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/02/2021] [Accepted: 12/02/2021] [Indexed: 11/02/2022]
Abstract
Bruton's tyrosine kinase (BTK) is an attractive target for the treatment of malignancy and inflammatory/autoimmune diseases. Most of the covalent BTK inhibitors would induce off-target side effects and drug resistance. To improve the drug safety of BTK inhibitors, non-covalent inhibitors have attracted more and more attention. We designed a series of novel pyrido[3,4-b]indol-1-one derivatives (N-A and N-B) via scaffold hopping from CGI-1746. The structure-activity relationship (SAR) of the newly-synthesized compounds was explored. The results showed that compounds 12 and 18 exhibited potent enzymatic potency against BTK with IC50 values of 0.22 μM and 0.19 μM, respectively. In lymphoma cell lines U-937 cells and Ramos cells, compounds 12 and 18 displayed comparative antiproliferative activity with Ibrutinib. Moreover, compound 12 induced G1-phase cell cycle arrest and apoptosis in U-937 cells. And it could effectively inhibit tumor growth in U-937 xenograft mouse model (TGI = 41.90% at 50 mg/kg). In all, the new pyrido[3,4-b]indol-1-one derivatives have the antitumor potency by BTK inhibition and were worthy of further exploration.
Collapse
Affiliation(s)
- Dou Dou
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
| | - Wenjie Sha
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
| | - Yanyan Diao
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
| | - Rongrong Su
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
| | - Yunjin Qiao
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
| | - Zhixiao Yu
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
| | - Zhenjiang Zhao
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
| | - Honglin Li
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
| | - Zhuo Chen
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
| | - Yufang Xu
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
| |
Collapse
|
|
41
|
Xie H, Appelt JW, Jenkins RW. Going with the Flow: Modeling the Tumor Microenvironment Using Microfluidic Technology. Cancers (Basel) 2021; 13:cancers13236052. [PMID: 34885161 PMCID: PMC8656483 DOI: 10.3390/cancers13236052] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/20/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The clinical success of cancer immunotherapy targeting immune checkpoints (e.g., PD-1, CTLA-4) has ushered in a new era of cancer therapeutics aimed at promoting antitumor immunity in hopes of offering durable clinical responses for patients with advanced, metastatic cancer. This success has also reinvigorated interest in developing tumor model systems that recapitulate key features of antitumor immune responses to complement existing in vivo tumor models. Patient-derived tumor models have emerged in recent years to facilitate study of tumor–immune dynamics. Microfluidic technology has enabled development of microphysiologic systems (MPSs) for the evaluation of the tumor microenvironment, which have shown early promise in studying tumor–immune dynamics. Further development of microfluidic-based “tumor-on-a-chip” MPSs to study tumor–immune interactions may overcome several key challenges currently facing tumor immunology. Abstract Recent advances in cancer immunotherapy have led a paradigm shift in the treatment of multiple malignancies with renewed focus on the host immune system and tumor–immune dynamics. However, intrinsic and acquired resistance to immunotherapy limits patient benefits and wider application. Investigations into the mechanisms of response and resistance to immunotherapy have demonstrated key tumor-intrinsic and tumor-extrinsic factors. Studying complex interactions with multiple cell types is necessary to understand the mechanisms of response and resistance to cancer therapies. The lack of model systems that faithfully recapitulate key features of the tumor microenvironment (TME) remains a challenge for cancer researchers. Here, we review recent advances in TME models focusing on the use of microfluidic technology to study and model the TME, including the application of microfluidic technologies to study tumor–immune dynamics and response to cancer therapeutics. We also discuss the limitations of current systems and suggest future directions to utilize this technology to its highest potential.
Collapse
Affiliation(s)
- Hongyan Xie
- Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (H.X.); (J.W.A.)
| | - Jackson W. Appelt
- Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (H.X.); (J.W.A.)
| | - Russell W. Jenkins
- Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (H.X.); (J.W.A.)
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA 02215, USA
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Correspondence: ; Tel.: +617-726-9372; Fax: +844-542-5959
| |
Collapse
|
|
42
|
Cuesta-Mateos C, Terrón F, Herling M. CCR7 in Blood Cancers - Review of Its Pathophysiological Roles and the Potential as a Therapeutic Target. Front Oncol 2021; 11:736758. [PMID: 34778050 PMCID: PMC8589249 DOI: 10.3389/fonc.2021.736758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 10/12/2021] [Indexed: 11/23/2022] Open
Abstract
According to the classical paradigm, CCR7 is a homing chemokine receptor that grants normal lymphocytes access to secondary lymphoid tissues such as lymph nodes or spleen. As such, in most lymphoproliferative disorders, CCR7 expression correlates with nodal or spleen involvement. Nonetheless, recent evidence suggests that CCR7 is more than a facilitator of lymphatic spread of tumor cells. Here, we review published data to catalogue CCR7 expression across blood cancers and appraise which classical and novel roles are attributed to this receptor in the pathogenesis of specific hematologic neoplasms. We outline why novel therapeutic strategies targeting CCR7 might provide clinical benefits to patients with CCR7-positive hematopoietic tumors.
Collapse
Affiliation(s)
- Carlos Cuesta-Mateos
- Immunology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria- Instituto la Princesa (IIS-IP), Madrid, Spain.,Immunological and Medicinal Products (IMMED S.L.), Madrid, Spain.,Catapult Therapeutics BV, Lelystad, Netherlands
| | - Fernando Terrón
- Immunological and Medicinal Products (IMMED S.L.), Madrid, Spain.,Catapult Therapeutics BV, Lelystad, Netherlands
| | - Marco Herling
- Clinic of Hematology and Cellular Therapy, University of Leipzig, Leipzig, Germany
| |
Collapse
|
|
43
|
Kriegelstein M, Hroch M, Marek A. Synthesis of [ 13 C 6 ]-ibrutinib. J Labelled Comp Radiopharm 2021; 64:500-512. [PMID: 34478181 DOI: 10.1002/jlcr.3944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/20/2021] [Accepted: 08/31/2021] [Indexed: 11/10/2022]
Abstract
Convenient and straightforward synthesis of ibrutinib labeled by carbon-13 isotope is reported. Isotopically labeled building block is introduced in the last step of reaction sequence affording sufficient isolated yield (7%) of [13 C6 ]-ibrutinib calculated towards starting commercially available [13 C6 ]-bromobenzene.
Collapse
Affiliation(s)
- Michal Kriegelstein
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
| | - Miloš Hroch
- Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Aleš Marek
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
| |
Collapse
|
|
44
|
Mateu-Albero T, Juárez-Sánchez R, Loscertales J, Mol W, Terrón F, Muñoz-Calleja C, Cuesta-Mateos C. Effect of ibrutinib on CCR7 expression and functionality in chronic lymphocytic leukemia and its implication for the activity of CAP-100, a novel therapeutic anti-CCR7 antibody. Cancer Immunol Immunother 2021; 71:627-636. [PMID: 34297159 DOI: 10.1007/s00262-021-03014-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 07/08/2021] [Indexed: 02/01/2023]
Abstract
CAP-100 is a novel therapeutic antibody directed against the ligand binding site of human CCR7. This chemokine receptor is overexpressed in chronic lymphocytic leukemia (CLL) and orchestrates the homing of CLL cells into the lymph node. Previous studies, on a very limited number of samples, hypothesized that the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib might induce loss of surface CCR7 levels in CLL cells. CAP-100 will be evaluated in clinical trials as a therapy for relapse/refractory CLL patients, who have received at least two systemic therapies (NCT04704323). As nowadays many relapse/refractory CLL patients will have received ibrutinib as a prior therapy, we aimed to investigate in a large cohort of CLL patients the impact of this BTKi on CCR7 expression and functionality as well as on the therapeutic activity of CAP-100. Our data confirm that ibrutinib moderately down-regulates the very high expression of CCR7 in CLL cells but has no apparent effect on CCR7-induced chemotaxis. Moreover, CLL cells are perfectly targetable by CAP-100 which led to a complete inhibition of CCR7-mediated migration and induced strong target cell killing through antibody-dependent cell-mediated cytotoxicity, irrespective of previous or contemporary ibrutinib administration. Together, these results validate the therapeutic utility of CAP-100 as a next-line single-agent therapy for CLL patients who failed to ibrutinib and confirm that CAP-100 and ibrutinib have complementary non-overlapping mechanisms of action, potentially allowing for combination therapy.
Collapse
Affiliation(s)
- Tamara Mateu-Albero
- Immunology Department, Hospital Universitario de La Princesa, IIS-IP, Diego de León 62, 28006, Madrid, Spain
| | - Raquel Juárez-Sánchez
- Immunology Department, Hospital Universitario de La Princesa, IIS-IP, Diego de León 62, 28006, Madrid, Spain.,IMMED S.L., Immunological and Medicinal Products, C/ Velázquez 57, 6º derecha, 28001, Madrid, Spain
| | - Javier Loscertales
- Hematology Department, Hospital Universitario de La Princesa, IIS-IP, Diego de León 62, 28006, Madrid, Spain
| | - Wim Mol
- Catapult Therapeutics, Lelystad, The Netherlands
| | - Fernando Terrón
- IMMED S.L., Immunological and Medicinal Products, C/ Velázquez 57, 6º derecha, 28001, Madrid, Spain.,Catapult Therapeutics, Lelystad, The Netherlands
| | - Cecilia Muñoz-Calleja
- Immunology Department, Hospital Universitario de La Princesa, IIS-IP, Diego de León 62, 28006, Madrid, Spain.,Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
| | - Carlos Cuesta-Mateos
- Immunology Department, Hospital Universitario de La Princesa, IIS-IP, Diego de León 62, 28006, Madrid, Spain. .,IMMED S.L., Immunological and Medicinal Products, C/ Velázquez 57, 6º derecha, 28001, Madrid, Spain. .,Catapult Therapeutics, Lelystad, The Netherlands.
| |
Collapse
|
|
45
|
Grassilli E, Cerrito MG, Bonomo S, Giovannoni R, Conconi D, Lavitrano M. p65BTK Is a Novel Biomarker and Therapeutic Target in Solid Tumors. Front Cell Dev Biol 2021; 9:690365. [PMID: 34164404 PMCID: PMC8215537 DOI: 10.3389/fcell.2021.690365] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 05/07/2021] [Indexed: 12/30/2022] Open
Abstract
Bruton’s tyrosine kinase (BTK) is a non-receptor intracellular kinase playing a key role in the proliferation and survival of normal and malignant B-lymphocytes. Its targeting by Ibrutinib, the first specific inhibitor, represented a turning point for the therapy of certain types of B-cell leukemias/lymphomas and several more BTK inhibitors are today in the clinic or advanced clinical trials. BTK expression was successively found to occur also outside of the hematopoietic compartment. In fact, we identified p65BTK, a novel 65 kDa isoform lacking an N-term stretch of 86 amino acids (compared to the 77 kDa protein expressed in B cells) as highly expressed in colon cancer patients. We demonstrated that p65BTK is a powerful oncogene acting downstream of the RAS/MAPK pathway and necessary for RAS-mediated transformation. Notably, the kinase domain is conserved and therefore inhibited by the available BTK-targeting drugs (Ibrutinib, Spebrutinib, etc.) which we used to demonstrate that p65BTK is an actionable target in drug-resistant colorectal carcinomas. We found p65BTK expressed also in >50% non-small cell lung cancers (NSCLC) and demonstrated that it is an actionable target in KRAS-mutated/EGFR-wild type drug-resistant NSCLC models (for which no targeted therapy is available). We also reported a significant correlation between p65BTK expression and low-grade tumors and overall survival of patients with grade III gliomas and showed that its targeting induced a significant decrease in the viability of in glioma stem cells. Finally, in ovarian cancer patients, p65BTK expression levels correlate with early relapse and shorter progression-free survival, both indicators of resistance to therapy. Remarkably, Ibrutinib is more effective than standard of care (SOC) therapeutics in in vitro and ex vivo settings. On the whole, our preclinical data indicate that, depending on the tumor type, BTK inhibitors used alone can induce cytotoxicity (gliomas), be more effective than SOC chemotherapy (ovarian cancer) or can kill drug-resistant tumor cells when used in combination with SOC chemotherapy (colon cancer and NSCLC) or targeted therapy (NSCLC and ovarian cancer), thus suggesting that p65BTK may be an actionable target in different solid tumors. In addition, our data also give the proof-of-concept for starting clinical trials using BTK inhibitors, alone or in combination, to improve the therapeutic options for solid tumors treatment.
Collapse
Affiliation(s)
- Emanuela Grassilli
- Laboratory of Molecular Medicine, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Maria Grazia Cerrito
- Laboratory of Molecular Medicine, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Sara Bonomo
- Laboratory of Molecular Medicine, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Roberto Giovannoni
- Laboratory of Molecular Medicine, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Donatella Conconi
- Laboratory of Molecular Medicine, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Marialuisa Lavitrano
- Laboratory of Molecular Medicine, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| |
Collapse
|
|
46
|
Wang X, Wang Z, Fan X, Yan M, Jiang L, Xia Y, Cao J, Liu Y. Comparison of the drug-drug interactions potential of ibrutinib and acalabrutinib via inhibition of UDP-glucuronosyltransferase. Toxicol Appl Pharmacol 2021; 424:115595. [PMID: 34038714 DOI: 10.1016/j.taap.2021.115595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/18/2021] [Accepted: 05/21/2021] [Indexed: 11/26/2022]
Abstract
Ibrutinib and acalabrutinib are two Bruton's tyrosine kinase (BTK) inhibitors which have gained Food and Drug Administration (FDA) approval for the treatment of various B cell malignancies. Herein, we investigated the effects of the two drugs on UDP-glucuronosyltransferase (UGT) activities to evaluate their potential risk for drug-drug interactions (DDIs) via UGT inhibition. Our data indicated that ibrutinib exerted broad inhibition on most of UGTs, including a potent competitive inhibition against UGT1A1 with a Ki value of 0.90 ± 0.03 μM, a noncompetitive inhibition against UGT1A3 and UGT1A7 with Ki values of 0.88 ± 0.03 μM and 2.52 ± 0.23 μM, respectively, while acalabrutinib only exhibited weak UGT inhibition towards all tested UGT isoforms. DDI risk prediction suggested that the inhibition against UGT1A1 and UGT1A3 by ibrutinib might bring a potential DDIs risk, while acalabrutinib was unlikely to trigger clinically significant UGT-mediated DDIs due to its weak effects. Our study raises an alarm bell about potential DDI risk associated with ibrutinib, however, the extrapolation from in vitro data to in vivo drug interactions should be taken with caution, and additional systemic study is needed.
Collapse
Affiliation(s)
- Xiaoyu Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Zhe Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Xiaoyu Fan
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Mingrui Yan
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Lili Jiang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Yangliu Xia
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Jun Cao
- Department of Occupational and Environmental Health, Dalian Medical University, Dalian 116044, China.
| | - Yong Liu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China.
| |
Collapse
|
|
47
|
Huang J, Zhang L, Wan D, Zhou L, Zheng S, Lin S, Qiao Y. Extracellular matrix and its therapeutic potential for cancer treatment. Signal Transduct Target Ther 2021; 6:153. [PMID: 33888679 PMCID: PMC8062524 DOI: 10.1038/s41392-021-00544-0] [Citation(s) in RCA: 424] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 02/17/2021] [Accepted: 03/09/2021] [Indexed: 02/07/2023] Open
Abstract
The extracellular matrix (ECM) is one of the major components of tumors that plays multiple crucial roles, including mechanical support, modulation of the microenvironment, and a source of signaling molecules. The quantity and cross-linking status of ECM components are major factors determining tissue stiffness. During tumorigenesis, the interplay between cancer cells and the tumor microenvironment (TME) often results in the stiffness of the ECM, leading to aberrant mechanotransduction and further malignant transformation. Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment. Herein, we summarized the knowledge concerning the following: (1) major ECM constituents and their functions in both normal and malignant conditions; (2) the interplay between cancer cells and the ECM in the TME; (3) key receptors for mechanotransduction and their alteration during carcinogenesis; and (4) the current therapeutic strategies targeting aberrant ECM for cancer treatment.
Collapse
Affiliation(s)
- Jiacheng Huang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Lele Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Dalong Wan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Shengzhang Lin
- School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, 310000, China.
| | - Yiting Qiao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China.
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China.
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China.
| |
Collapse
|
|
48
|
Long MJC, Rogg C, Aye Y. An Oculus to Profile and Probe Target Engagement In Vivo: How T-REX Was Born and Its Evolution into G-REX. Acc Chem Res 2021; 54:618-631. [PMID: 33228351 DOI: 10.1021/acs.accounts.0c00537] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Here we provide a personal account of innovation and design principles underpinning a method to interrogate precision electrophile signaling that has come to be known as "REX technologies". This Account is framed in the context of trying to improve methods of target mining and understanding of individual target-ligand engagement by a specific natural electrophile and the ramifications of this labeling event in cells and organisms. We start by explaining from a practical standpoint why gleaning such understanding is critical: we are constantly assailed by a battery of electrophilic molecules that exist as a consequence of diet, food preparation, ineluctable endogenous metabolic processes, and potentially disease. The resulting molecules, which are detectable in the body, appear to be able to modify function of specific proteins. Aside from potentially being biologically relevant in their own right, these labeling events are essentially identical to protein-covalent drug interactions. Thus, on what proteins and even in what ways a covalent drug will work can be understood through the eyes of natural electrophiles; extending this logic leads to the postulate that target identification of specific electrophiles can inform on drug design. However, when we entered this field, there was no way to interrogate how a specific labeling event impacted a specific protein in an unperturbed cell. Methods to evaluate stoichiometry of labeling, and even chemospecificity of a specific phenotype were limited. There were further no generally accepted ways to study electrophile signaling that did not hugely disturb physiology.We developed T-REX, a method to study single-protein-specific electrophile engagement, to interrogate how single-protein electrophile labeling shapes pathway flux. Using T-REX, we discovered that labeling of several proteins by a specific electrophile, even at low occupancy, leads to biologically relevant signaling outputs. Further experimentation using T-REX showed that in some instances, single-protein isoforms were electrophile responsive against other isoforms, such as Akt3. Selective electrophile-labeling of Akt3 elicited inhibition of Akt-pathway flux in cells and in zebrafish embryos. Using these data, we rationally designed a molecule to selectively target Akt3. This was a fusion of the naturally derived electrophile and an isoform-nonspecific, reversible Akt inhibitor in phase-II trials, MK-2206. The resulting molecule was a selective inhibitor of Akt3 and was shown to fare better than MK-2206 in breast cancer xenograft mouse models. Recently, we have also developed a means to screen electrophile sensors that is unbiased and uses a precise burst of electrophiles. Using this method, dubbed G-REX, in conjunction with T-REX, we discovered new DNA-damage response upregulation pathways orchestrated by simple natural electrophiles. We thus emphasize how deriving a quantitative understanding of electrophile signaling that is linked to thorough and precise mechanistic studies can open doors to numerous medicinally and biologically relevant insights, from gleaning better understanding of target engagement and target mining to rational design of targeted covalent medicines.
Collapse
Affiliation(s)
- Marcus J. C. Long
- Department of Molecular Biology, University of Geneva, 30 quai Ernest-Ansermet, 1211 Geneva, Switzerland
| | - Chloé Rogg
- Institute of Chemical Sciences and Engineering (ISIC), Swiss Federal Institute of Technology Lausanne (EPFL), Route Cantonale, 1015 Lausanne, Switzerland
| | - Yimon Aye
- Institute of Chemical Sciences and Engineering (ISIC), Swiss Federal Institute of Technology Lausanne (EPFL), Route Cantonale, 1015 Lausanne, Switzerland
| |
Collapse
|
|
49
|
K. Bhanumathy K, Balagopal A, Vizeacoumar FS, Vizeacoumar FJ, Freywald A, Giambra V. Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia. Cancers (Basel) 2021; 13:cancers13020184. [PMID: 33430292 PMCID: PMC7825731 DOI: 10.3390/cancers13020184] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Protein phosphorylation is a key regulatory mechanism that controls a wide variety of cellular responses. This process is catalysed by the members of the protein kinase superfamily that are classified into two main families based on their ability to phosphorylate either tyrosine or serine and threonine residues in their substrates. Massive research efforts have been invested in dissecting the functions of tyrosine kinases, revealing their importance in the initiation and progression of human malignancies. Based on these investigations, numerous tyrosine kinase inhibitors have been included in clinical protocols and proved to be effective in targeted therapies for various haematological malignancies. In this review, we provide insights into the role of tyrosine kinases in leukaemia and discuss their targeting for therapeutic purposes with the currently available inhibitory compounds. Abstract Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.
Collapse
Affiliation(s)
- Kalpana K. Bhanumathy
- Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; (A.B.); (F.J.V.)
- Correspondence: (K.K.B.); (V.G.); Tel.: +1-(306)-716-7456 (K.K.B.); +39-0882-416574 (V.G.)
| | - Amrutha Balagopal
- Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; (A.B.); (F.J.V.)
| | - Frederick S. Vizeacoumar
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; (F.S.V.); (A.F.)
| | - Franco J. Vizeacoumar
- Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; (A.B.); (F.J.V.)
- Cancer Research Department, Saskatchewan Cancer Agency, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada
| | - Andrew Freywald
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; (F.S.V.); (A.F.)
| | - Vincenzo Giambra
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy
- Correspondence: (K.K.B.); (V.G.); Tel.: +1-(306)-716-7456 (K.K.B.); +39-0882-416574 (V.G.)
| |
Collapse
|
|
50
|
Simultaneous measurement of acalabrutinib, ibrutinib, and their metabolites in beagle dog plasma by UPLC-MS/MS and its application to a pharmacokinetic study. J Pharm Biomed Anal 2020; 191:113613. [DOI: 10.1016/j.jpba.2020.113613] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/01/2020] [Accepted: 09/02/2020] [Indexed: 12/26/2022]
|